In the following discussion certain articles and methods will be described for background and introductory purposes. Nothing contained herein is to be construed as an “admission” of prior art. Applicant expressly reserves the right to demonstrate, where appropriate, that the articles and methods referenced herein do not constitute prior art under the applicable statutory provisions.
Multiple sclerosis (MS) is a complex neurological disease characterized by deterioration of central nervous system (CNS) myelin. Myelin is an insulating material composed primarily of lipids that protects nerve fibers—axons—that transmit electric impulses throughout the body. Demyelination of axons in MS results in axon degeneration and neuronal cell death, but more specifically MS destroys oligodendrocytes, specialized glial cells that generate and maintain myelin.
Oligodendrocyte progenitors are generated in ventral areas of the developing brain from a glial progenitor. Oligodendrocyte progenitors actively migrate and proliferate, populating the CNS, eventually maturing to target and extend myelin sheaths along the axons. However, a subpopulation of the oligodendrocyte progenitors remains as resident, undifferentiated cells to play a role if myelin is damaged or deteriorates.
People with MS suffer attacks when T-cells cross the blood brain barrier and attack the myelin sheath that coats axons of the CNS. This disruption should induce the maturation of the subpopulation of oligodendrocyte progenitors that has remained in the CNS to repair damaged myelin. Instead, however, it has been found that people with MS have oligodendrocyte progenitors that tend not to mature into oligodendrocytes after myelin damage, resulting in inadequate myelin repair.
Cell transplantation therapies have been proposed to treat neurodegenerative diseases such as MS, cerebral palsy and Parkinson's Disease; yet wide-spread application of cell-based therapies depends on the availability of sufficient amounts of the proper types of, e.g., oligodendrocyte progenitor cells. One possibility for providing such cells is using embryonic stem cells, for example, see Bjorklund, et al., Nat. Neurosci. 3:537-44 (2000) (studies relating to Parkinson's disease). Embryonic stem cells can be expanded to virtually unlimited numbers and have the potential to generate all types of cells in culture; however, embryonic stem cell-based therapy is complicated by, amongst other things, immune rejection due to immunological incompatibility between the patient and donor. Alternatively, successful generation of cloned stem cells by somatic cell nuclear transfer creates the possibility of generating genetically identical “customized” cells by using donor cells from a patient as the source of the nucleus, thereby eliminating the requirement for immune suppression (see Hochedlinger, et al., N. Engl. J. Med. 349:275-86 (2003)); however, technical and logistical impediments of the nuclear transfer procedure complicate the practical realization of somatic cell nuclear transfer in humans.
Production of large populations of glial cells that are not complicated by patient immunological incompatibility would prove invaluable in studies of CNS myelination, disease modeling, and drug screening. More importantly, promoting remyelination using these cells in cell-based therapies has enormous implications in regenerative medicine. The present invention provides such glial cells, and methods for the generation thereof.